We propose to continue and expand our ongoing prospective investigation on prediagnostic serological markers of infection and risk of MS. During the first period of this project, we have found evidence that a significant increase in serum antibodies to the Epstein-Barr Virus (EBV) occurs years before the onset of the first symptoms of multiple sclerosis (MS). In contrast, serum titers of anti-Chlamydia pneumoniae (Cpn) were not significantly related to risk of MS. We now propose to expand our findings on EBV, to extend the investigation to human herpes virus 6 (HHV-6) and the hepatitis A virus, and to examine whether the presence of IgM antibodies to myelin oligodendrocyte glycoprotein (MOG) or myelin basic protein (MBP) in asymptomatic individuals predicts the risk of MS. The proposed investigation will continue to take advantage of the Department of Defense Serum Repository, a unique facility now comprising multiple serum samples collected from over 7 million US military personnel. In the first project period, we have only included in the study cases and controls from the Army. To increase the power of the study, we will now extend the identification of MS cases and selection of controls to the Navy. By this mean, and by extending the follow up for case identification to the year 2007, we expect to increase the number of cases to 501 and to extend the interval between the date of collection of the first blood samples to the onset of the first MS symptoms to over 10 years. This large sample size and the availability for each subject of serum samples collected at multiple points in time will allow sufficient power to examine the relationship between changes in the serological markers and risk of developing MS.